Fluorine atoms are often introduced into organic molecules to enhance their pharmacological properties such as solubility, metabolic and oxidative stability, lipophilicity, and bioavailability.[1] Among the fluorine containing functional groups, the trifluoromethoxy group (OCF3) is of current interest because of its unique structural and electronic properties, which can be useful in material, agricultural, and pharmaceutical science.[2] For example, one of the distinct structural features of trifluoromethoxylated arenes (Ar—OCF3) is that the OCF3 bond is orthogonal to the aryl ring.[3,1b] As a result, lone pair electrons on oxygen only weakly delocalize into the ring, which renders OCF3 an electron withdrawing group. In addition, the OCF3 group has one of the highest lipophilicity values (πx=1.04) compared to the CF3 (πx=0.88), CH3 (πx=0.52), F (πx=0.14), and OCH3 (πx=−0.02) groups.[4] Compounds with higher lipophilicity show enhancement in their in vivo uptake and transport in biological systems. Indeed, many OCF3 containing pharmaceuticals and agrochemicals show enhanced effectiveness often coupled with diminished side-effects (FIG. 1).[2a,2b,5]
Despite the intriguing properties of the OCF3 group, introduction of this functional group into organic molecules remains a challenge. Only a handful of transformations have been developed over the last few decades and most of them either suffer from poor substrate scope or require the use of highly toxic and/or thermally unstable reagents. A pioneering study by Yagupolskii and coworkers in 1955 led to the development of a two-step chlorination/chlorine-fluorine exchange protocol for the synthesis of simple aryl trifluoromethyl ethers.[6] In 1964, Sheppard reported an alternative approach involving reactions of aromatic or aliphatic alcohols with fluorophosgene followed by deoxyfluorination with tetrafluorosulfur (SF4).[7] About thirty years later, Hiyama synthesized aryl trifluoromethyl ethers via formation of dithiocarbonates followed by oxidative fluorodesulfurization.[8] Electrophilic trifluormethylations of alcohols and phenols have also been developed. Employing thermally labile O-trifluoromethyldibenzyl furanium salts, Umemoto and coworkers successfully trifluoro-methylated phenols to form aryl trifluoromethyl ethers.[9] An elegant direct trifluoromethylation of aliphatic alcohols using bench stable reagent was reported by Togni and coworkers.[10] However, poor yields were obtained for phenolic substrates due to the competing C-trifluoromethylation.[11] Most recently, a direct trifluoro-methoxylation of benzene employing toxic gaseous trifluoromethyl perfluorite[12a-b], and a transition metal-mediated trifluoro-methoxylation of aryl stannanes as well as aryl boronic acids utilizing thermally labile tris(dimethylamino)sulfonium trifluoro-methoxide have been developed.[2b] However, most of these approaches either suffer from poor substrate scope or require use of highly toxic and/or thermally labile reagents. As a result, many of OCF3-containing building blocks are prohibitively expensive (FIG. 1C).